Stable polymers that depolymerize rapidly on demand upon application of a specific stimulus are of great interest for a variety of industrial applications, such as patterning, cosmetics, agriculture and electronics, and in biomedical applications such as tissue engineering, tissue adhesives, and drug delivery. Despite this interest, few synthetic polymers have been identified that have the ability to degrade with high sensitivity in response to specific stimuli. Most current degradable materials are unresponsive to the often subtle changes found in biological systems or, in the case of photodegradable polymers, require long, intense irradiation that may not be biologically compatible. The ongoing need for specifically engineered polymers is clearly seen in the broad use of unresponsive poly(lactic-co-glycolic acid) (PLGA) in current medical materials.
The emerging technology of nanoparticles packaging offers a way to package and deliver compounds of interest that offers a number of advantages. Nanoparticles can be synthesized and/or assembled so as to enclose other compounds of interest. Thus, nanoparticles can serve to protect compounds of interest by sequestration and/or encapsulation. Nanoparticulate media involved in this approach include nano- and microgels, nano- and microspheres, polymer micelles, and polymerized liposomes. Retention of the active compound in the nanocarriers is achieved by physical entrapment or by thermodynamic forces such as hydrophobic interactions.
Non-limiting examples of compounds of interest for delivery via nanoparticles to an area of interest, such as tumor tissue, include bioactive agents, pharmaceutical agents, or imaging agents. Nanoparticles may be then signaled to release their contents via externally-applied signals and/or signals present at the area of interest. In some examples, nanoparticles may be delivered systematically to a patient, while releasing of the contents of the nanoparticle at a focused area of interest within a living organism. Non-limiting examples of the contents of nanoparticles, i.e., payloads, include pharmaceutical agents, drugs, antibodies, and/or labeling compounds.
Nanoparticle packaging can also improve the effectiveness of bioactive agents and/or pharmaceutical agents. In some nanoparticle designs, the serum stability of bioactive agents and/or pharmaceutical agents can be enhanced and solubility limitations bypassed. Thus, nanoparticle packaging circumvents the vulnerability of bioactive agents and/or pharmaceutical agents, for example, to a reduction in efficacy due to bioavailability problems, e.g., solubility and/or stability. Moreover, such carriers can also serve to minimize undesirable side effects by reducing systemic exposure to drugs and/or by decreasing their necessary dosage. In addition, encapsulating bioactive agents and/or imaging agents may protect them from sequestration and/or renal clearance.
Nanoparticles also offer the potential, at least, for targeted delivery of their payloads to specific areas of interest within a patient. For example, an affinity reagent attached externally to nanoparticles enables an increase the concentration of such nanoparticles at their intended location. An example of such an affinity reagent is an antibody. Modifying the nanoparticles, and not the payload itself, avoids direct modification of the enclosed bioactive agent while improving its targeting and therefore obviates concerns about changing the activity of the bioactive agent.
Nanoparticles may be designed to be capable of a controlled and rapid triggered response to physiological events and/or conditions. Such physiological events and/or conditions may include changes in extracellular pH, temperature and reactive oxygen species. Therefore, nanoparticles capable of such a triggered response may be useful in the delivery of therapeutics and diagnostics to diseased cells and tissue. (See, e.g., Farokhzad, et al., (2006) Expert Opinion on Drug Delivery, 3, 311-324; Farokhzad & Langer (2009) ACS Nano, 3, 16-20: Ferrari, (2005) Nat. Rev. Cancer 5, 161-171; Ganta, et al., (2008) J. Control. Release, 126, 187-204; Langer (1990) Science, 249, 1527-33; LaVan, et al. (2003) Nat. Biotechnol. 21, 1184-1191; Whitesides (2003) Nat. Biotechnol. 21, 1161-1165; and Zhang et al. (2008) Clinical Pharmacology and Therapeutics, 83, 761-9).
Additionally, encapsulation within nanoparticles constructed from biodegradable polymers can allow bioactive agents to be delivered to the cytosol of diseased cells via endosomes and cytosolic release (Lewis (1990) Drugs and the Pharmaceutical Sciences, Vol. 45: Biodegradable Polymers as Drug Delivery Systems, Chasin & Langer, Eds.; Marcel Dekker, pp 1-42; Panyam & Labhasetwar (2003) Adv. Drug Delivery. Rev., 55, 329-347; and Shenoy, et al. (2005) Pharm. Res., 22, 2107-14.). Cytosolic delivery is particularly challenging and can be a major hurdle for effective therapeutic delivery (Vasir & Labhasetwar (2007) Adv. Drug Delivery. Rev., 59, 718-728; and Mescalchin et al. (2007) Expert Opin. Biol. Ther., 7, 1531-1538). Burst-degrading drug delivery systems hold promise in achieving increased cytosolic release through elevated osmotic pressure within the endosomes (Sonawane, et al. (2003) J. Biol. Chem. 2003, 278, 44826-31; and Hu, et al. (2007) Nano Lett. 7, 3056-64).
In the past, nanoparticles have been developed from hydrogels utilizing ketal crosslinks. However the payloads of such nanoparticles are usually limited to large water-soluble macromolecules. Unfortunately, with nanoparticles such as these, significant unwanted degradation occurs at physiological pH values over time (Cohen, et al. (2008) Bioconjug. Chem., 19, 876-81). Similarly, hydrophobic polyketals can encapsulate both hydrophobic and hydrophilic payloads, however, as nanoparticles they no longer undergo rapid acid catalyzed hydrolysis unless fully hydrated (Yang, et al. (2008) Bioconjug. Chem., 19, 1164-1169).
Formulation of nanoparticles from polymers may provide them with a hydrophobic character. However, this dramatically slows down their hydrolysis degradation kinetics as degradation only occurs slowly by a surface erosion mechanism (Heffernan, et al. (2009) Biomaterials, 30, 910-918; Heffernan & Murthy (2005) Bioconjug. Chem., 16, 1340-1342; Paramonov, et al. (2008) Bioconjug. Chem., 19, 911-919).
There is growing interest in polymeric biomaterials that can be remotely disassembled in a controlled fashion with an external stimulus, but are otherwise stable under physiological conditions (Wang, W.; Alexander, C. Angew. Chem. Int. Ed., 2008, 47, 7804-7806). Various internal and external stimuli, such as specific enzymes, temperature, ultrasound, and electromagnetic radiation, have been exploited as release mechanisms. (See, e.g., Veronese, et al. (2005) Bioconjugate Chem. 16, 775-784; Chung, et al. (1999) Controlled Release, 62 (1-2), 115-27; Liu, et al. (2005) Biomaterials, 26, 5064-5074; Na, et al. (2006) Eur. J. Pharm. Sci., 27, 115-122; Gao, et al. (2005) Controlled Release, 102, 203-22; Nelson, et al. (2002) Cancer Research, 62, 7280-83); and PCT Publication WO 2011/038117 A2, Almutairi et al.)
Nanoparticles composed of synthetic polymers such as poly(lactic-co-glycolic acid) (PLGA) are safe and attractive methods for DNA delivery applications and have been used in several studies. PLGA polyesters can be degraded by hydrolysis, facilitating their widespread use in medicine and biomedical research. Their dependence on slow hydrolysis makes for long degradation times (half-life of one year in vivo), thus limiting their applicability. While degradation can be sped up by copolymerization with more hydrophilic monomers; degradation is still too slow for triggered release or degradation.
Polylactide (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) have been thoroughly investigated as drug delivery vehicles because of their slow hydrolytic degradation to largely biologically innocuous substances, but these polymers offer minimal control over degradation. Molecular engineering of the PLGA structures would accelerate degradation rates and allow triggered degradation.